Background: Children
born to condylomatous mothers are at risk for developing
juvenile-onset recurrent respiratory papillomatosis (JORRP). We
inquired if the triad of vaginal delivery, being first-born, and
maternal age of less than 20 years are also risk factors for
JORRP.

Methods: Data for
JORRP and adult-onset (AO) RRP cases were obtained from
questionnaires answered by patients or their parents for the
Recurrent Respiratory Papillomatosis Foundation. The observed numbers
of cesarean births, first order births, and births to mothers less
than 20 years old were compared with expected numbers for the same
variables, which were computed by distributing the cases by year of
birth and then applying to them national annual statistics for the
year of birth. In addition, observed and expected numbers of first
order births to mothers less than 20 years old were compared with
corresponding numbers in mothers 20 years old or older.

Results: In JORRP
cases, the relationships between observed and expected numbers of
cases were as follows: cesarean births, 4.6 fold less; first order
births, 1.6 fold greater; maternal age less than 20 years old, 2.6
fold greater. All these differences were statistically highly
significant. The observed parity effect was mediated to a large
extent by maternal age. In contrast, there were no significant
differences between observed and expected numbers of AORRP cases with
respect to any of the above variables.

Conclusions: Young,
primiparous mothers with condylomas are at a high risk for
transmission of JORRP to their infants. The option of cesarean
delivery should be discussed with a mother who has condyloma at the
time of delivery.

Introduction

JORRP is a rare disease,
with a recent estimate of about 2,300 cases, annually, in the
USA.1 The papillomas are histologically benign neoplasms,
which often recur after surgical removal and can produce sudden
respiratory obstruction and become life-threatening. In the most
severe cases, swift regrowth necessitates surgical operations as
often as every 2-4 weeks. The disease may fluctuate in severity and
may enter remission after several years, or persist into adulthood.
The disease is most common on the vocal folds but may extend to other
sites (trachea, lung) in the respiratory tract. In rare instances,
the papilloma may undergo malignant transformation.

The etiologic link between
maternal condyloma at delivery and JORRP in the infant was first
recognized by Hajek2 in a case report in 1956. This
observation was supported by additional case reports3 and
by the finding that more than 50% of mothers of JORRP cases gave a
history of having condylomas during pregnancy and/or at
delivery.4,5 Subsequent virologic studies fully
substantiated the link between genital condylomas and JORRP. HPV
types 6 and 11 which are responsible for 80-90% of the condylomas are
documented in nearly 100% of JORRP.6-8 Transmission of the
virus from mother to infant is believed to occur predominantly
intrapartum, as the fetus passes through an infected birth
canal.2 Cases of JORRP rarely give a history of cesarean
birth, an indication that cesarean delivery decreases the risk of
acquiring JORRP.9 Adult-onset RRP (AORRP) is also caused
by infection with HPV-6 and HPV-11 but very probably, the infection
is not acquired at birth.10

Genital tract infection with
HPV-6 and HPV-11 is common, but JORRP is rare. Data are not available
to make a reliable estimate of the risk of transmission from an
infected mother to a child but this risk is perceived to be
low.9-11 It has been suggested that a finer definition of
a high-risk birth would be helpful in considering cesarean delivery
for the prevention of JORRP.1,9,12,13

Epidemiologic investigations
of JORRP and AORRP have been difficult because of the rarity of the
disease. In a recent case control study of 26 JORRP and 33 AORRP
cases at Johns Hopkins Hospital, it was found that the triad of
vaginal delivery, being first-born and having a teenage mother were
risk factors for JORRP but not for AORRP.10 A larger data
base became available when in 1992, RRP patients and their families,
in collaboration with otolaryngologists and other interested
investigators nationwide, created the Recurrent Respiratory
Papillomatosis Foundation (RRPF) to provide support to patients and
their families, to serve as a resource for information about RRP, and
to aid in efforts for the prevention and treatment of
RRP.14 In this report, we compare JORRP and AORRP cases in
the RRPF data base with national statistics with respect to the triad
of probable risk factors for JORRP, viz., (1) manner of delivery
(vaginal or cesarean), (2) being first-born, and (3) maternal age
less than 20 years.

Methods

RRP Cases: The RRP
Newsletter, a twice a year publication of the RRPF (RRP Foundation,
PO Box 6643, Lawrenceville, NJ 08648-0643), provides a detailed and
continuing account of recruitment of patients and the status of the
RRPF database. The patient information used in this study was
collected from answers to questionnaires designed by the RRPF and
completed by the patients and parents of underage patients. The RRPF
has located and surveyed RRP patients in the USA primarily through
their attending otolaryngologists. The RRPF questionnaires were sent
to otolaryngologists who distributed them to their RRP patients, with
a request to complete and return them to the RRPF. The respondents
have given written informed consent to allow the use of the
information in the questionnaire for research.

For this study, the
following information was extracted from the RRPF database: age at
RRP diagnosis; year of birth; manner of delivery (vaginal or
cesarean); age of mother at the time of the patient's birth; and
birth order. Patients were classified as JORRP if their age at
diagnosis (approximation for age of onset of disease) was 14 years or
less and as AORRP if their age at diagnosis was greater than 14
years.1 There were no cases diagnosed at 15, 16 and 17
years of age. The proportion of JORRP cases diagnosed by the ages of
1 year, 2 years, 3 years and 5 years were 29%, 58%, 71% and 88%,
respectively. Questions regarding maternal age and birth order were
added later to the questionnaire, so information about these
variables was available from fewer patients than information about
age at diagnosis and type of delivery. Only one JORRP and five AORRP
cases from Johns Hopkins Hospital who could have possibly
participated in the case-control study reported
previously10 were registered with RRPF, so there was
little overlap between the two studies.

National statistics:
Annual cesarean rates from 1965 to 1994 were obtained from
publications based on National Center for Health Statistics (NCHS)
Surveys.15-18 Annual data for the same years, on
proportion of all births that were first order births, that were born
to mothers younger than 20 years, and that were first order births
born to mothers stratified by age (less than 20 and equal to or
greater than 20) were obtained from vital statistics publications
from NCHS.19

Statistics: For each
of the variables (cesarean birth, first birth order, maternal age
less than 20 years, and first order birth in mothers stratified by
age), the expected number of JORRP and AORRP cases were computed by
first distributing the cases by year of birth and then applying
national annual statistics to cases born in that year. All cases born
before 1970 were grouped in a single category and the national
statistics for 1965 were applied to these births. The expected
numbers of cases were compared with the actual numbers of cases using
the Z test for proportions.

Results

Cesarean births: The
national cesarean birth rate increased rapidly from 5.5% in 1970 to
greater than 20% in 1983, peaked at 24.7% in 1988 and has since
declined gradually to 23.0% in 1994. Among the patients surveyed, a
large majority of the JORRP patients (77%) were born after 1980,
whereas most of AORRP cases (94%) were born before 1970 (Table 1).
The observed number of cesarean births in JORRP cases (6 births) was
about 4.6 fold less than the expected number (27.4 births); this
difference was statistically highly significant (p < 0.0001)
(Table 1). In contrast, the difference between observed and expected
numbers of cesarean births in AORRP cases was not statistically
significant (Table 1).

We were able to make
telephone contact with the mothers of three of the six JORRP cases
who were born by cesarean delivery in 1987 and 1988. According to
their recollection, in all three instances, cesarean delivery was
performed after the labor pains had started and after the rupture of
the amniotic membranes.

Maternal age and birth
order: The national data on percentage of children who are (1)
first-born, (2) born to mothers less than 20 years, and (3)
first-born to mothers younger than 20 years were examined. The
percentage of children who are first-born increased from 30.8% in
1965 to 38.8% in 1970 and has remained steady around 40% since then,
whereas children born to mothers under the age of 20 years has
declined from 19.7% in 1973 to 13.1% in 1994. Approximately 10.2% of
children born in 1994 were first-births to mothers under the age of
20.

The observed number of JORRP
cases who were first-born (85 cases) was 1.6 times greater than the
expected number (51.4), a difference which was statistically highly
significant (p < 0.001) (Table 2). The number of JORRP cases born
to mothers younger than 20 years was 2.6 times greater than the
expected number (33 vs. 13.6); this difference was also statistically
highly significant (p < 0.002) (Table 2). Because of the known
high correlation between maternal age and parity, we compared the
observed and expected numbers of first births for mothers <20
years old and mothers > 20 years old (Table 2). The
observed births were 2.7 times higher for mothers <20 years old (p
< 0.002), but only 1.3 times higher for women >20 years
old (p = 0.29) (Table 2). In contrast, the observed and expected
numbers of AORRP cases were not significantly different for any of
these variables.

Discussion

The study revealed a sharp
contrast between JORRP and AORRP with respect to risk factors. For
each of the variables examined, AORRP cases were not significantly
different from national statistics whereas JORRP cases were markedly
different from national statistics. These results confirm the
findings of an earlier case-control study10 and indicate
that JORRP and AORRP, while they are caused by the same HPV types,
are very likely acquired under different circumstances.

The rarity of cesarean
delivery in JORRP cases is indirect evidence that the cases may be
preventable by cesarean delivery. We have previously reported one
case of cesarean birth when 10 would have been expected.9
In the present communication, we confirmed the rarity of cesarean
births in JORRP cases; there were six cases delivered by cesarean,
when 27 would have been expected. In at least three instances, the
cesarean section was performed after onset of labor and after rupture
of membranes, raising the possibility that in these cases, the fetus
could have been exposed to virus after membrane rupture. More direct
and objective evidence for the protective effect of timely cesarean
delivery could be obtained from a randomized clinical trial in women
who have condylomas at delivery. However, given the rarity of the
disease, the many years of necessary follow-up and, most important,
the ethical dilemma of having a control group which would not have
the option of having a cesarean delivery, it is questionable that
such a trial can or should be conducted. For similar reasons, it will
not be possible to compare directly the importance of clinical
condylomas relative to subclinical HPV-6/11 infections of the genital
tract for the occurrence of JORRP.

The data presented in our
study identify being first-born, and birth to a teenage mother as
additional risk factors for JORRP. Ten percent of U.S.
births,21 but 28% of JORRP cases, are first-born children
to teenage mothers. Our finding that primiparous women older than 20
years were not at significantly increased risk of having a child with
JORRP suggests that the observed parity effects are to a large extent
mediated by maternal age. One limitation of the study is that these
results are based on information provided by families who registered
with the RRPF. Therefore, the findings of this study need to be
evaluated for their generalizability by investigation of cases in
population-based RRP registries, which are being set up in some
regions in the USA (Armstrong et al., abstract presented at the 16th
International Papillomavirus Conference, September, 1997, Siena,
Italy). The conclusions are biologically plausible. The prevalence of
condylomas may be higher in young mothers, and young women may be
undergoing primary infection when the viral burden, and therefore the
risk of transmission, is the highest. The risk of intrapartum
transmission of herpes simplex virus, type 2, is very high (1 in 3)
when the infection is primary, but is reduced 10-fold or more, when
it is recurrent.22 The longer labor in first order birth
could potentially increase the time of contact between the fetus and
infected maternal secretions.

Cesarean birth is generally
not offered to a mother who has condylomas because the risk of JORRP
to a child born to a condylomatous mother is perceived to be very
low.9,13,20 The guideline on perinatal care of the
American College of Obstetricians and Gynecologists states that
"cesarean delivery is not recommended solely to protect the neonate
from HPV infection".11 We have estimated that the risk of
transmission of JORRP from a condylomatous mother to an infant may be
1-3%,12 and could be as high as 8% for first-born children
of teenage mothers (Bishai et al., unpublished data). The assumptions
on which these estimates are made, as well as other considerations
(e.g., maternal morbidity due to cesarean delivery, cost-benefit
analysis of cesarean delivery), need to be debated before a
population-wide policy regarding the prevention of JORRP by cesarean
deliveries is instituted, but personal choice is a different matter.
It is highly probable that some women at risk would be willing to
personally incur the extra expense and operative risk of cesarean
delivery to eliminate a 1%-8% chance of JORRP in their child. The
principle of autonomy would suggest that information regarding a
possible benefit be disclosed to patients who are at
risk.23 The need for cesarean delivery would be lessened
if an effective treatment for condylomas, suitable for pregnant
women, were available. Several new approaches toward prevention and
treatment of condylomas are promising.24,25 Any treatment
that would reduce the HPV viral burden in the genital tract during
labor, or diminish fetal contact with maternal virus, would likely
decrease the incidence of JORRP.

Acknowledgements

This study was supported in
part by Public Health Service grant U19 AI38533 (KVS) and the
Recurrent Respiratory Papillomatosis Foundation (WFS).